Factor IX inhibitors in haemophilia B: A report of National Haemophilia Registry in China.

INTRODUCTION: The development of inhibitors against factor FIX (FIX) is the most serious complication of FIX replacement therapy in haemophilia B (HB) patients. Currently, only few cohorts of HB inhibitor patients have been reported worldwide. AIM: This Chinese nationwide study of HB inhibitor patients explored their risk factors for FIX inhibitor development and experience on their management. METHODS: We retrospectively analysed patient characteristics, F9 genotypes, treatment strategies and outcomes of HB inhibitor patients registered to the Chinese National Registry and Patient Organization Registry. RESULTS: Forty-four unique HB inhibitor patients were identified in 4485 unique HB patients registered by year 2021 to the two Registries. Inhibitor diagnosis were usually delayed and the low prevalence (.98%) may suggest some inhibitor patients were not identified. Their median age at inhibitor diagnosis was 7.5 (IQR, 3.0-14.8) years. Most patients (95.5%) had high-titre inhibitors. Allergic/Anaphylactic reactions occurred in 59.1% patients. Large deletions and nonsense mutations were the most common F9 mutation types in our FIX inhibitor patients. Patients with large F9 gene deletions were more likely to develop inhibitors (p = .0002), while those with missense mutations had a low risk (p < .0001). Thirteen (29.5%) patients received immune tolerance induction (ITI) therapy using low-dose prothrombin complex concentrate regimens. Twelve completed ITI with three (25.0%) achieving success. Nephrotic syndrome developed in two (16.7%) patients during ITI. CONCLUSION: This study reports the largest Chinese cohort of HB inhibitor patients. Large deletions were most significantly associated with inhibitor development. Low-dose ITI might be feasible for FIX inhibitor eradication.

The rapid Bethesda assay is equivalent to the standard Bethesda assay for detection of factor IX inhibitors in patients with severe haemophilia B.

INTRODUCTION: The time-dependent nature of factor VIII (FVIII) inhibitors is well described, and the standard FVIII Bethesda assay used to measure inhibitors incorporates a 2-hour incubation. Despite case reports and reviews describing the immediate-acting nature of factor IX (FIX) inhibitors, many coagulation laboratories continue to use a traditional prolonged incubation for FIX Bethesda assays. To our knowledge, a comprehensive evaluation of the FIX Bethesda assay without incubation has not been reported. AIM: The goal of this study was to evaluate the performance of a rapid FIX Bethesda (ie no incubation) compared with the standard Bethesda assay (2-hour incubation). METHODS: The analysis used a Bethesda assay configured for either immediate testing or a 2-hour incubation. Samples from 14 haemophilia B patients with inhibitors and 9 non-human controls were tested. RESULTS: The two assays yielded similar performance overall. The average per cent difference in inhibitor titre between the rapid and standard FIX Bethesda assay was -3% (range -15% to +13%; P = .175) for patient samples and -2% (range -17% to +14%; P = .376) for controls. CONCLUSION: The rapid Bethesda assay showed good agreement with the standard Bethesda assay for determination of inhibitor levels in patients with severe haemophilia B. The rapid assay allows for faster assessment of inhibitors in patients with severe haemophilia B and has the potential to improve the ability of the coagulation laboratory to perform testing from a logistical viewpoint. Further studies involving larger numbers of patients would be important to confirm our findings.

Rituximab for treating inhibitors in people with inherited severe hemophilia.

BACKGROUND: Hemophilia A and B are inherited coagulation disorders characterized by a reduced or absent level of factor VIII or factor IX respectively. The severe form is characterized by a factor level less than 0.01 international units (IU) per milliliter. The development of inhibitors in hemophilia is the main complication of treatment, because the presence of these antibodies, reduces or even nullifies the efficacy of replacement therapy, making it very difficult to control the bleeding. People with inhibitors continue to have significantly higher risks of morbidity and mortality, with considerable treatment costs. Given the wide 'off-label' use of rituximab for treating people with hemophilia and inhibitors, its efficacy and safety need to be evaluated. This is an update of a previously published Cochrane Review. OBJECTIVES: To assess the efficacy and safety of rituximab for treating inhibitors in people with inherited severe hemophilia A or B. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, complied from electronic database searches and handsearching of journals and conference abstract books. We searched the reference lists of relevant articles and reviews and also searched for ongoing or unpublished studies. We also undertook further searches of other bibliographic databases and trial registries. Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register: 19 March 2020. SELECTION CRITERIA: Randomized controlled trials and controlled clinical trials investigating the efficacy and safety of rituximab for treating inhibitors in people with hemophilia. DATA COLLECTION AND ANALYSIS: No randomized controlled trials matching the selection criteria were eligible for inclusion. MAIN RESULTS: No randomized controlled trials on rituximab for treating inhibitors in people with hemophilia were identified. AUTHORS' CONCLUSIONS: We were unable to identify any relevant trials on the efficacy and safety of rituximab for treating inhibitors in people with hemophilia. The research evidence available is from case reports and case series. Randomized controlled trials are needed to evaluate the efficacy and safety of rituximab for this condition. However, prior to the publication of any possible future randomized controlled trials, meta-analysis of case reports and case series may provide some evidence.

Factors IX, XI, and XII: potential therapeutic targets for anticoagulant therapy in atherothrombosis.

Atherosclerosis is a leading cause of cardiovascular and neurological ischemic events. Plaque rupture leads to the exposure of highly thrombogenic material with blood and results in the activation of the coagulation cascade, thrombus formation, and embolic events. Although antiplatelets and anticoagulants are used to prevent thromboembolic episodes, bleeding episodes remain the major adverse effect. Decreased ischemic events have been reported while comparing oral rivaroxaban and apixaban with aspirin to improve the therapeutic outcome in several clinical trials, including Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51, Apixaban for Prevention of Acute Ischemic and Safety Events, and GEMINI-ACS-1 phase II clinical trials. However, there were bleeding episodes. Thus, there is an unmet need for better therapeutic strategies. Therefore, the current focus is to target Factors IX, XI, and XII to develop safer and efficient strategies. In this article, we critically reviewed and discussed the limitations of current therapies and the potential of targeting Factors IX, XI, and XII for anticoagulant therapy in atherothrombosis.

A natural choice for hemophilia B.

In this issue of Blood, Crudele et al describe a novel study of adeno-associated virus (AAV) vector-mediated gene therapy that induced immune tolerance to factor IX (FIX) in a hemophilia B (HB) dog with previously formed anti-FIX inhibitor antibodies (IAs).

AAV liver expression of FIX-Padua prevents and eradicates FIX inhibitor without increasing thrombogenicity in hemophilia B dogs and mice.

Emerging successful clinical data on gene therapy using adeno-associated viral (AAV) vector for hemophilia B (HB) showed that the risk of cellular immune response to vector capsid is clearly dose dependent. To decrease the vector dose, we explored AAV-8 (1-3 × 10(12) vg/kg) encoding a hyperfunctional factor IX (FIX-Padua, arginine 338 to leucine) in FIX inhibitor-prone HB dogs. Two naïve HB dogs showed sustained expression of FIX-Padua with an 8- to 12-fold increased specific activity reaching 25% to 40% activity without antibody formation to FIX. A third dog with preexisting FIX inhibitors exhibited a transient anamnestic response (5 Bethesda units) at 2 weeks after vector delivery following by spontaneous eradication of the antibody to FIX by day 70. In this dog, sustained FIX expression reached ∼200% and 30% of activity and antigen levels, respectively. Immune tolerance was confirmed in all dogs after challenges with plasma-derived FIX concentrate. Shortening of the clotting times and lack of bleeding episodes support the phenotypic correction of the severe phenotype, with no clinical or laboratory evidence of risk of thrombosis. Provocative studies in mice showed that FIX-Padua exhibits similar immunogenicity and thrombogenicity compared with FIX wild type. Collectively, these data support the potential translation of gene-based strategies using FIX-Padua for HB.

Rituximab for treating inhibitors in people with inherited severe hemophilia.

BACKGROUND: Hemophilia A and B are inherited coagulation disorders characterized by a reduced or absent level of factor VIII or factor IX respectively. The severe form is characterized by a factor level less than 0.01 international units (IU) per milliliter. The development of inhibitors in hemophilia is the main complication of treatment, because the presence of these antibodies, reduces or even nullifies the efficacy of replacement therapy, making it very difficult to control the bleeding. People with inhibitors continue to have significantly higher risks of morbidity and mortality, with considerable treatment costs. Given the wide 'off-label' use of rituximab for treating people with hemophilia and inhibitors, its efficacy and safety need to be evaluated. This is an update of a previously published Cochrane Review. OBJECTIVES: To assess the efficacy and safety of rituximab for treating inhibitors in people with inherited severe hemophilia A or B. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, complied from electronic database searches and handsearching of journals and conference abstract books. We searched the reference lists of relevant articles and reviews and also searched for ongoing or unpublished studies. We also undertook further searches of other bibliographic databases and trial registries.Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register: 16 February 2017. SELECTION CRITERIA: Randomized controlled trials and controlled clinical trials investigating the efficacy and safety of rituximab for treating inhibitors in people with hemophilia. DATA COLLECTION AND ANALYSIS: No randomized controlled trials matching the selection criteria were eligible for inclusion. MAIN RESULTS: No randomized controlled trials on rituximab for treating inhibitors in people with hemophilia were identified. AUTHORS' CONCLUSIONS: We were unable to identify any relevant trials on the efficacy and safety of rituximab for treating inhibitors in people with hemophilia. The research evidence available is from case reports and case series. Randomized controlled trials are needed to evaluate the efficacy and safety of rituximab for this condition. However, prior to the publication of any possible future randomized controlled trials, meta-analysis of case reports and case series may provide some evidence.

5'-(E)-Vinylphosphonate: A Stable Phosphate Mimic Can Improve the RNAi Activity of siRNA-GalNAc Conjugates.

Small interfering RNA (siRNA)-mediated silencing requires siRNA loading into the RNA-induced silencing complex (RISC). Presence of 5'-phosphate (5'-P) is reported to be critical for efficient RISC loading of the antisense strand (AS) by anchoring it to the mid-domain of the Argonaute2 (Ago2) protein. Phosphorylation of exogenous duplex siRNAs is thought to be accomplished by cytosolic Clp1 kinase. However, although extensive chemical modifications are essential for siRNA-GalNAc conjugate activity, they can significantly impair Clp1 kinase activity. Here, we further elucidated the effect of 5'-P on the activity of siRNA-GalNAc conjugates. Our results demonstrate that a subset of sequences benefit from the presence of exogenous 5'-P. For those that do, incorporation of 5'-(E)-vinylphosphonate (5'-VP), a metabolically stable phosphate mimic, results in up to 20-fold improved in vitro potency and up to a threefold benefit in in vivo activity by promoting Ago2 loading and enhancing metabolic stability.

Rituximab for treating inhibitors in people with inherited severe hemophilia.

BACKGROUND: Hemophilia A and B are inherited coagulation disorders characterized by a reduced or absent level of factor VIII or factor IX respectively. The severe form is characterized by a factor level less than 0.01 international units (IU) per milliliter. The development of inhibitors in hemophilia is the main complication of treatment, because the presence of these antibodies, reduces or even nullifies the efficacy of replacement therapy, making it very difficult to control the bleeding. People with inhibitors continue to have significantly higher risks of morbidity and mortality, with considerable treatment costs. Given the wide 'off-label' use of rituximab for treating people with hemophilia and inhibitors, its efficacy and safety need to be evaluated. OBJECTIVES: To assess the efficacy and safety of rituximab for treating inhibitors in people with inherited severe hemophilia A or B. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, complied from electronic database searches and handsearching of journals and conference abstract books. We searched the reference lists of relevant articles and reviews and also searched for ongoing or unpublished studies.Date of last search: 27 January 2015. SELECTION CRITERIA: Randomized controlled trials and controlled clinical trials investigating the efficacy and safety of rituximab for treating inhibitors in people with hemophilia. DATA COLLECTION AND ANALYSIS: No randomized controlled trials matching the selection criteria were eligible for inclusion. MAIN RESULTS: No randomized controlled trials on rituximab for treating inhibitors in people with hemophilia were identified. AUTHORS' CONCLUSIONS: We were unable to identify any relevant trials on the efficacy and safety of rituximab for treating inhibitors in people with hemophilia. The research evidence available is from case reports and case series. Randomized controlled trials are needed to evaluate the efficacy and safety of rituximab for this condition. However, prior to the publication of any possible future randomized controlled trials, meta-analysis of case reports and case series may provide some evidence.

Inhibitor eradication with rituximab in haemophilia: where do we stand?

Rituximab is a humanized chimeric anti-CD20 monoclonal antibody initially developed for the treatment of some haematological malignancies. Thanks to its ability to rapidly and specifically deplete B cells, it has also been used in a variety of autoimmune disorders, haematological or not. In this context, during the last decade several small case series have documented successful inhibitor eradication with rituximab, alone or in combination with other immunosuppressive agents, in patients with acquired haemophilia A refractory to standard therapy. In addition, a number of investigators have recently used this agent in patients with congenital haemophilia A or B and alloantibodies refractory to first-line treatment. This article critically reviews the current knowledge on the use of rituximab in acquired haemophilia or congenital haemophilia complicated by alloantibodies, also providing treatment algorithms for the management of these conditions.

Prevalent inhibitors in haemophilia B subjects enrolled in the Universal Data Collection database.

Several risk factors for inhibitors have recently been described for haemophilia A. It has been assumed that similar risk factors are also relevant for haemophilia B, but there is limited data to confirm this notion. The aim of this study was to determine the prevalence of and risk factors associated with inhibitors in haemophilia B. The database of the Universal Data Collection (UDC) project of the Centers for Disease Control for the years 1998-2011 was queried to determine the prevalence of inhibitors in haemophilia B subjects. In addition, disease severity, race/ethnicity, age, factor exposure and prophylaxis usage were evaluated to determine their impact on inhibitor prevalence. Of the 3785 male subjects with haemophilia B enrolled in the UDC database, 75 (2%) were determined to have an inhibitor at some point during the study period. Severe disease (OR 13.1, 95% CI 6.2-27.7), black race (OR 2.2, 95% CI 1.2-4.1), and age <11 years (OR 2.5, 95% CI 1.5-4.0) were found to be significantly associated with having an inhibitor. There was insufficient data to determine if type of factor used and prophylaxis were associated with inhibitors. Inhibitors in haemophilia B are much less prevalent than haemophilia A, especially in patients with mild disease. Similar factors associated with inhibitors in haemophilia A also seem to be present for haemophilia B. The information collected by this large surveillance project did not permit evaluation of potential risk factors related to treatment approaches and exposures, and additional studies will be required.

Renal thromboembolism during treatment with recombinant activated factor VII (rFVIIa) in a child with hemophilia B with factor IX inhibitors.

BACKGROUND: Serious thromboembolic events connected with rFVIIa therapy in hemophilia patients are rare. Only three cases are reported in children, all of them with hemophilia A. CASE PRESENTATION: We present unique case of patient with hemophilia B and high titer inhibitors to coagulation FIX, who developed severe renal damage due to thromboembolic event during rFVIIa therapy, associated with unsuspected renovascular anomalies. CONCLUSION: Caution is necessary if hematuria B requires administration of rFVIIa. US color doppler renal imaging before and after drug administration should be sufficient as an early warning.

FEIBA versus NovoSeven in hemophilia patients with inhibitors.

The management of patients with congenital hemophilia who develop alloantibodies that neutralize coagulation factor activity is the most important challenge for hemophilia care providers because this complication renders replacement treatment with factor concentrates partially or completely ineffective, exposing the patients to an increased risk of morbidity and mortality. Development of inhibitors complicates the clinical course of severe hemophilia in up to 30% of patients with hemophilia A and up to 5% of those with hemophilia B. Although the ultimate goal of treatment of patients with alloantibodies against factors VIII and IX is eradication of the inhibitor, the control of bleeding through high doses of factor concentrates (low titer inhibitors) or bypassing agents (high titer inhibitors) is the mainstay of management of these patients. In this review, we summarize the main characteristics of the bypassing agents FEIBA and NovoSeven, briefly discussing available literature data, and in particular, focusing on comparative studies.

Comprehensive care of the patient with haemophilia and inhibitors undergoing surgery: practical aspects.

Congenital haemophilia is a rare and complex condition for which dedicated specialized and comprehensive care has produced measurable improvements in clinical outcomes and advances in patient management. Among these advances is the ability to safely perform surgery in patients with inhibitor antibodies to factors VIII and IX, in whom all but the most necessary of surgeries were once avoided due to the risk for uncontrollable bleeding due to ineffectiveness of replacement therapy. Nevertheless, surgery continues to pose a major challenge in this relatively rare group of patients because of significantly higher costs than in patients without inhibitors, as well as a high risk for bleeding and other complications. Because of the concentration of expertise and experience, it is recommended that any surgery in patients with haemophilia and inhibitors be planned in conjunction with a haemophilia treatment centre (HTC) and performed in a hospital that incorporates a HTC. Coordinated, standard pre-, intra- and postoperative assessments and planning are intended to optimize surgical outcome and utilization of resources, including costly factor concentrates and other haemostatic agents, while minimizing the risk for bleeding and other adverse consequences both during and after surgery. This article will review the special considerations for patients with inhibitors as they prepare for and move through surgery and recovery, with an emphasis on the roles and responsibilities of individual members of the multidisciplinary team in facilitating this process.

Inhibitors in haemophilia B: the Italian experience.

The prevalence of inhibitors in haemophilia B is significantly lower than that of patients with haemophilia A. However, the peculiar occurrence of allergic reactions associated with the onset of inhibitor in haemophilia B (HB) may render immune tolerance a risky procedure. We have carried out a detailed survey among all the Italian Hemophilia Centers to analyse all the patients with HB and inhibitors. A total of eight patients were reported among 282 living patients (2.8%) with severe factor IX (FIX) deficiency (FIX < 1 U dL(-1)). In addition, two deceased patients were also identified. Six patients carried nonsense mutations while in four partial or complete gene deletions were detected. Three patients (one deceased) had history of allergic/anaphylactic reaction upon substitutive treatment, which in one case was recurrent and resolved after switching to plasma derived FIX. Immune tolerance was adopted in five patients and in four complete response was achieved while in the remaining it was partial. No nephrotic syndrome was observed. Our data confirm that inhibitors in HB occur in patients with null mutations or complete/partial gene deletion. Immune tolerance can be achieved also in HB patients, without allergic reactions or nephrotic syndrome upon replacement therapy.

Patient-reported outcomes of 182 adults with severe haemophilia in Germany comparing prophylactic vs. on-demand replacement therapy.

Clotting factor replacement therapy has a major impact on the quality of life in patients with haemophilia. To analyse and compare the outcomes of on-demand and prophylactic treatment regimens in child- and adulthood, a self-evaluation questionnaire was sent to 182 patients over 30 years of age with severe haemophilia A or B. Analysis of the questionnaire results revealed that most study participants had been treated on-demand in childhood, but that the majority of these patients subsequently switched to prophylaxis. However, of those patients who began with prophylaxis as children, the vast majority maintained prophylactic treatment as adults. Inhibitor development was reported significantly more frequently by patients who started with on-demand treatment than by those who started with prophylaxis. In the year prior to completing the questionnaire, adults with severe haemophilia who received prophylactic treatment reported a significantly lower incidence of bleeding as a result of more frequent factor consumption. These results are in close accordance with published prospective data. Although nearly all patients with severe haemophilia had joint pain due to bleeding, those who had always had prophylactic treatment reported superior outcomes in terms of the need for joint replacement, walking speed and distance, participation in school sports and further education. These data clearly underline the superiority of prophylactic treatment for the majority of individuals with severe haemophilia. The worst outcomes were found in those treated on-demand in childhood who later switched to prophylaxis. In contrast to most studies which have compared treatment regimens on the basis of data from healthcare professionals, this study reflects treatment outcomes from the patient's perspective.

No inhibitor development after continuous infusion of factor concentrates in subjects with bleeding disorders undergoing surgery: a prospective study.

Inhibitor development against von Willebrand factor, factor VIII or factor IX is one of the most severe complications of treating patients with von Willebrand's disease (VWD), haemophilia A or haemophilia B respectively. Continuous infusion of factor concentrate has been implicated as a risk factor for inhibitor development. This prospective study investigated inhibitor development after continuous infusion of factor concentrate for surgical procedures in subjects with VWD or a severe form of haemophilia (factor activity <1%). Observations were made on the occurrence of inhibitor formation, adverse events and virus seroconversions. Main inclusion criteria comprised a negative history of inhibitors to replacement factor concentrate, ≥ 50 exposure days to factor concentrate and anticipated surgery requiring replacement factor coverage for ≥ 3 days. Therapy began with a bolus dose of 30-50 IU kg(-1) body weight of factor concentrate followed by continuous infusion with 3-4 IU kg(-1) h(-1) . Continuous infusion dose of factor concentrate was adjusted based on factor levels measured at least once daily. In 46 subjects included in the study to date, no inhibitors have been identified at discharge or follow-up (3-4 weeks after surgery), and no thrombotic events or postoperative wound infections occurred. All subjects underwent surgery without major blood loss, and hemostatic efficacy was generally rated 'excellent'. The results of the current study are promising, although the number of subjects is too small to make a definitive statement about the incidence of inhibitor development during continuous infusion of factor concentrate. Therefore, this study will be continued.

Successful management of factor IX inhibitor-associated nephrotic syndrome in a hemophilia B patient.

BACKGROUND: Nephrotic syndrome (NS) is a recognized complication of immune tolerance induction (ITI) therapy, a treatment strategy used to treat inhibitors in patients with hemophilia B receiving factor IX concentrate. CASE DIAGNOSIS/TREATMENT: We present a 4-year-old boy with hemophilia B and an inhibitor who underwent ITI, and developed NS 19 months into this therapy. A percutaneous renal biopsy was safely performed with factor IX (FIX) concentrate administration both preceding and following the procedure. The patient's inhibitor level had increased to 1.4-1.6 Bethesda Units just prior to the onset of proteinuria. Histology confirmed segmental membranous nephropathy (MGN). The patient was continued on FIX concentrate as ITI and also received 4 weekly doses of rituximab and ongoing immunosuppression with mycophenolate mofetil. This resulted in the complete resolution of his inhibitor and his NS. He continues with a modified ITI regimen and remains inhibitor-free without proteinuria >12 months post-biopsy. CONCLUSIONS: Hemophilia B patients undergoing ITI should be regularly screened for NS. At first detection of proteinuria, with proper precautions, a percutaneous kidney biopsy can be performed safely in patients with low levels of inhibitor. Our patient had segmental MGN with complete remission of NS.

Oral delivery of bioencapsulated coagulation factor IX prevents inhibitor formation and fatal anaphylaxis in hemophilia B mice.

To address complications of pathogenic antibody or life-threatening anaphylactic reactions in protein replacement therapy for patients with hemophilia or other inherited protein deficiencies, we have developed a prophylactic protocol using a murine hemophilia B model. Oral delivery of coagulation factor IX fused with cholera toxin beta-subunit (with or without a furin cleavage site; CTB-FFIX or CTB-FIX), expressed in chloroplasts (up to 3.8% soluble protein or 0.4 mg/g leaf tissue), bioencapsulated in plant cells, effectively blocked formation of inhibitory antibodies (undetectable or up to 100-fold less than controls). Moreover, this treatment eliminated fatal anaphylactic reactions that occurred after four to six exposures to intravenous F.IX. Whereas only 20-25% of control animals survived after six to eight F.IX doses, 90-93% of F.IX-fed mice survived 12 injections without signs of allergy or anaphylaxis. Immunostaining confirmed delivery of F.IX to Peyer's patches in the ileum. Within 2-5 h, feeding of CTB-FFIX additionally resulted in systemic delivery of F.IX antigen. This high-responder strain of hemophilia B mice represents a new animal model to study anaphylactic reactions. The protocol was effective over a range of oral antigen doses (equivalent to 5-80 microg recombinant F.IX/kg), and controlled inhibitor formation and anaphylaxis long-term, up to 7 months (approximately 40% life span of this mouse strain). Oral antigen administration caused a deviant immune response that suppressed formation of IgE and inhibitory antibodies. This cost-effective and efficient approach of antigen delivery to the gut should be applicable to several genetic diseases that are prone to pathogenic antibody responses during treatment.